Parathyroid hormone-related protein regulates cell survival pathways via integrin α6β4-mediated activation of phosphatidylinositol 3-kinase/Akt signaling

Vandanajay Bhatia, Ramanjaneya V. Mula, Nancy L. Weigel, Miriam Falzon

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Parathyroid hormone-related protein (PTHrP) is expressed by human prostatic tissues and cancer cell lines. PTHrP enhances tumor cell growth and metastasis in vivo and up-regulates proinvasive integrin α6β 4 expression in vitro. Hallmarks of malignant tumor cells include resistance to apoptosis and anchorage-independent cell growth. In this study, we used the human prostate cancer cell lines C4-2 and PC-3as model systems to study the effects of PTHrP on these processes. We report that PTHrP protects these cells from doxorubicin-induced apoptosis and promotes anchorage- independent cell growth via an intracrine pathway. Conversely, autocrine/paracrine PTHrP action increases apoptosis in C4-2 cells and has no effect on apoptosis in PC-3cells. The intracrine effects of PTHrP on apoptosis are mediated via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. PTHrP also affects the phosphorylation state of Akt substrates implicated in apoptosis suppression, including glycogen synthase kinase-3and Bad. The prosurvival effects of PTHrP are accompanied by increases in the ratio of antiapoptotic to proapoptotic members of the Bcl-2 family and in levels of c-myc. PTHrP also increases nuclear factor-κB activity via a PI3K-dependent pathway. Integrin α6β4 is known to activate PI3K. Here, we also show that knockdown of integrin α6β4 negates the PTHrP-mediated activation of the PI3K/Akt pathway. Taken together, these observations provide evidence of a link between PTHrP and the PI3K/Akt signaling pathway through integrin α6β4, resulting in the activation of survival pathways. Targeting PTHrP production in prostate cancer may thus prove therapeutically beneficial.

Original languageEnglish (US)
Pages (from-to)1119-1131
Number of pages13
JournalMolecular Cancer Research
Volume7
Issue number7
DOIs
StatePublished - Jul 2009

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ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

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